This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Tyrosine phosphorylation is an important signal that tightly regulates many cellular responses mediated by the immune system. Protein tyrosine phosphatases (PTP) antagonize these key signal transduction pathways though their intrinsic dephosphorylation activity. Intracellular pathogens, such as Mycobacterium tuberculosis (Mtb), may secrete PTPs to evade host responses or achieve immune escape. The catalytic mechanisms, cellular functions and host substrates of the two Mtb PTPs (PtpA and PtpB) are largely unknown. I will investigate PtpB?s autoinhibitory lid, a structural feature that blocks potential substrates as well as reactive oxygen species (ROS) access to the protein?s active site. I will structurally characterize the conformational changes that occur when the lid opens, how oxidation affects the open and closed forms of the protein, and protein bound to inhibitors that may block mycobacterial infection and persistence. These studies will provide a greater mechanistic understanding of Mtb PTPs and their role in interfering with host signaling. The protein constructs used in these studies will include wild-type, wild-type oxidized, lid opening mutants, lid opening mutants-oxidized, and deleted lid protein with and without inhibitor.